ACR CONVERGENCE 2020—How does the body’s microbiome affect inflammatory diseases, such as rheumatoid arthritis (RA)? Can diet alter a patient’s microbiome or metabolome enough to improve symptoms or disease activity? In November at ACR Convergence 2020, two researchers discussed their laboratories’ efforts to answer these questions and, hopefully, provide evidencebased dietary advice to patients.
The Microbiome & Systemic Health
In chronic, inflammatory diseases, such as RA, the interplay of a patient’s environment, microbial exposures and immune system is an intriguing area to explore, said Curtis Huttenhower, PhD, professor of computational biology and bioinformatics at the Harvard T.H. Chan School of Public Health, Boston.
“The links between the microbiome and chronic disease are most obvious in the gastrointestinal tract, where the majority of microbes reside. But the same is true throughout the body, as microbes rest on the skin, or in the joints or oral cavity,” Dr. Huttenhower said.
Transmitted through the human immune system, these microorganisms may have an effect on arthritis symptoms, such as joint pain or inflammation, or more systemic phenotypes, such as the gut-brain axis. Antibiotics and other drugs can alter the gut microbiome, and the same is true for dietary compounds.
“There’s been a lot of work on the direct effects of diet on the microbiome [because] it contributes to human metabolism. But the microbiome also has an indirect effect on our dietary components that changes things like circulating metabolites, blood sugar responses and blood lipids, all of which can have effects on systemic health. We don’t know how it works yet, but the microbiome is a promising mechanism to monitor and improve health,” said Dr. Huttenhower.
Dr. Huttenhower’s laboratory studies microbiome epidemiology and its contributions to health on a population-wide scale, mostly associations between the microbiome and inflammatory bowel disease (IBD) and colorectal cancer. They want to develop a consistent perspective on what features of the microbiome relate to particular microbial exposures and health outcomes, and to understand what drives these relationships.
“Then, we can take population-scale human observations back to a more lab-controlled model, such as animal studies or in vitro microbial cultures, to get a mechanistic perspective on how these interactions might be causal, and how you can modify these aspects of the microbiome to improve disease outcomes,” he said.
New Arthritis Initiative
Dr. Huttenhower is an associate member of the Inflammatory Arthritis Microbiome Consortium (IAMC), which is conducting a multi-year study at four centers in England that began in April 2016. Researchers are recruiting patients with RA, ankylosing spondylitis (AS), psoriatic arthritis (PsA) and juvenile idiopathic arthritis (JIA). They are also conducting experiments on mice to study subjects’ microbiomes, how microbiome biomarkers may predict disease outcomes or therapy responses, and which individual microbes may worsen or protect against inflammatory disease. He shared some early findings from their research.
The study has recruited 117 RA, 34 PsA and 98 AS patients, along with 54 patients with non-inflammatory joint pain and 134 healthy controls, ranging in age from their 20s–80s. (JIA patients are being recruited for a separate study.) Patients provide blood and clinical information at a lab, then collect stool samples and fill out dietary surveys at home. C-reactive protein (CRP) levels, genetic profiling, fecal isolates, microbes and other data are collected.
So far, the data suggest increased inflammation does not correspond with major overall microbiome changes, “but if we zoom in closer, we see individual, smaller-scale associations between the microbiome and different aspects of arthritis phenotypes,” Dr. Huttenhower said. “This is typical in microbiome research: You have to look closely at individual [microorganisms] and individual phenotypes,” and in RA, microbial patterns are similar to those seen in IBD.
Example: Faecalibacterium prausnitzii, generally a beneficial, anti-inflammatory bug, appears to be depleted in the gut of RA patients at times of increasing inflammation. People without inflammation have higher levels of F. prausnitzii. The reverse is seen with typically bad, proinflammatory microorganisms, such as Ruminococcus gnavus, which result in inflamed patients having higher levels, while healthy controls have lower levels. Researchers have found fewer samples with an absence of R. gnavus in cases with systemic inflammation. However, not all R. gnavus microorganisms are alike.
“When we look at genetic variations in microbes from strain to strain, often there can be large swaths of the genome, with one-quarter to one-third of genes differing between strains of the same microbe. Microbial genetics are far more diverse than human genetics,” he said.
One interesting finding is a distinct subclade of nucleotide variance that defines related strains of R. gnavus enriched in both RA and AS patient populations. The researchers are trying to identify which genes are present or absent in particular R. gnavus strains and explain their role in inflammation. Many microbial genes in the human gut are biochemically uncharacterized.
“Often, we look at these genes and say, ‘Well, there’s a gene, but we don’t know what it does.’ But in subset of disease-associated microbial genes, we can start to hypothesize why they drive systemic inflammation or not,” said Dr. Huttenhower.
Microbes Fight for Iron
The IAMC researchers have also noticed an increase in iron sequestration utilization genes in the altered gut microbiomes of patients with inflammatory arthritis. Various pro-inflammatory microbes, including R. gnavus, seem to compete for iron as a limited resource, possibly to supplement their own growth and outcompete other microbes for the mineral, he said. The researchers also found an increase in microbes, using both local and diet-derived folate independent of methotrexate treatment, in the guts of people with more severe arthritis.
All of their findings suggest the microbiome may interact with our diets in many ways, but the direct effects of diet on the microbiome still seem modest. In the 2020 PREDICT 1 study of 1,102 U.S. and U.K. adults with chronic diseases, only daily coffee drinking seemed to have a stronger impact on levels of one gut bug, while most other dietary factors had smaller effects.1 In the 2020 Men’s Lifestyle Validation Study of 307 patients, the direct effect of dietary components, such as fiber intake, on the microbiome were modest overall.2
“Instead, the microbiome’s effect on diet-derived compounds and diet-derived phenotypes was much stronger. Even though fiber only slightly affected the microbiome directly, there was a very strong interaction between your microbiome configuration—in this case, carrying Prevotella copri—and the degree to which fiber intake was protective of systemic inflammation in the form of CRP levels,” said Dr. Huttenhower. “Individuals with P. copri already tended to have good CRP levels, whereas those lacking P. copri were more responsive to fiber intake as a protective factor.”
Most dietary components don’t directly change most microbiome components, but instead, your microbiome may change effects of nutrients, he concluded.
Arthritis Diet at Last?
RA patients often ask rheumatologist Monica Guma, MD, PhD, for dietary recommendations, because they perceive changes in their symptoms if they consume or avoid certain foods.
“People with RA know they have a chronic disease and that they will need chronic medications. They all seek additional sources of relief or treatments with fewer side effects,” including diet, said Dr. Guma, associate professor of medicine at the University of California, San Diego. “They all ask me questions like, ‘What diet would you recommend for me?’ or ‘Would a diet help me take fewer pills?’”
Dietary interventions have never been established as evidence-based complementary therapies in RA, so rheumatologists have no specific recommendations to reply to these questions.
Dr. Guma and her research team conducted a 28-day pilot feasibility study to explore how the diet composition of patients with RA may improve their symptoms, as well as alter their microbiome and/or metabolome, with results published in 2020.3 The small study had no placebo group. Based on past trials of RA patients following Mediterranean and vegetarian diet plans, they designed the ITIS diet to be full of potentially anti-inflammatory foods and practical to follow, she said.4,5 The new diet includes 20% of calories from proteins, 50% from carbohydrates and 30% from fats.
“We wanted our patients to focus on changing their habits. We didn’t want them to focus on losing weight, because we know this is often difficult for them,” said Dr. Guma.
‘People with RA know they have a chronic disease & that they will need chronic medications. They all seek additional sources of relief or treatments with fewer side effects,’ including diet, said Monica Guma, MD, PhD.
High Adherence Rate
In a two-week, pre-intervention phase, participants were asked to record what they normally ate. Patients were given physical exams, blood tests and the Health Assessment Questionnaire (HAQ) to measure disease activity, surveys to measure Visual Analogue Scale (VAS) pain and fatigue scores, and stool samples for metabolome and microbiome assessments.
The final study included 20 adults with diagnosed RA defined by the 2010 ACR/EULAR classification criteria who had at least three tender and three swollen joints. Patients who were pregnant or lactating, who already followed a vegetarian or vegan diet, or who required a medication change during the study period were excluded. Most participants were female and obese, and the median age was 57.1 years old. Higher baseline disease activity among participants correlated with a lower intake of anti-inflammatory foods and higher amounts of sugar-sweetened sodas, red meat, milk or gluten.
Participants were asked to follow the new eating plan for two weeks, although some continued for a week longer, and overall adherence was high, said Dr. Guma. Participants could choose from seven days’ worth of suggested meal plans with optional help from a dietitian. Daily menus included one mandatory smoothie, three meals and two snacks that included a mix of potentially anti-inflammatory ingredients, such as enzymatic fruits (e.g., mango, pineapple and papaya), plain yogurt with no added sugar, leafy green vegetables, oats, avocado, walnuts, honey, miso and lean proteins.
Participants were encouraged to try new ingredients, such as chia seeds, because they contain tryptophan, which is associated with a boost in serotonin for pain relief, as well as flaxseed, turmeric, ginger, black pepper or green tea. Patients were asked to eat red meat no more than twice a week, reduce dairy products other than yogurt—coconut and almond milk were suggested options for smoothies—and eat less gluten and nightshade vegetables.
After 14 days on the diet, participants had follow-up physical exams, blood and stool tests, and completed disease activity and health assessment questionnaires. Although their mean body mass index barely dipped from day 0 to 14—as expected—some patients had dramatic improvements in clinical symptoms, said Dr. Guma. Mean fatigue scores improved from 3.975 to 2.49, mean morning stiffness scores improved from 46.65 to 29.25, pain scores from 3.895 to 2.49, mean Clinical Disease Activity Index (CDAI) scores from 25.405 to 12.68, and Disease Activity Score-28 for RA with CRP (DAS28-CRP) scores from 3.715 to 2.619.
Metabolomic Diversity
Researchers also screened participants’ fecal samples with 165 rRNA gene sequencing. Although their microbiome diversity did not change much over two weeks, there was an early trend toward a more diverse metabolome after the diet intervention, said Dr. Guma.
Patients with better clinical responses, such as dramatic drops in pain scores, had a more diverse fecal microbiome at baseline compared to those with less symptomatic improvement. Metabolomic diversity was similar across all participants at baseline, but afterward, those with greater clinical responses at day 14 had more diversity of metabolites than those with milder responses. What made the difference?
The researchers concluded that strict diet adherence or having a healthier diet at baseline, with higher consumption of such foods as whole grains, fish or enzymatic fruits seemed to correlate with greater improvements in symptoms, such as pain.
Next, Dr. Guma and her laboratory team would like to compare outcomes of RA patients on the ITIS diet to the Mediterranean diet, or to follow patients on longer-duration dietary interventions to see if it may have a positive effect on their microbiome.
“With a longer diet, you may be able to really change the gut microbes to slowly achieve a better microbiome,” she said. “We want to see if that, together with the right pool of metabolites, would mean a better response.”
Susan Bernstein is a freelance journalist based in Atlanta.
References
- Spector T, Asnicar F, Berry S, et al. Microbiome signatures of nutrients, foods and dietary patterns: Potential for personalized nutrition from the PREDICT 1 study. Curr Dev Nutr. 2020 Jun;4(suppl 2):1587.
- Li J, Li Y, Ivey K, et al. Interplay between diet and gut microbiota, and circulating levels of trimethylamine N-oxide: Findings from the men’s lifestyle validation study [abstract P507]. Circulation. 2020 Mar 2;141(suppl 1):AP507.
- Bustamante MF, Augustin-Perez M, Cedola F, et al. Design of an anti-inflammatory diet (ITIS diet) for patients with rheumatoid arthritis. Contemp Clin Trials Commun. 2020 Jan 21;17:100524.
- Skoldstam L, Hagfors L, Johansson G. An experimental study of Mediterranean diet intervention for patients with rheumatoid arthritis. Ann Rheum Dis. 2003 Mar; 62(3):208–214.
- Kjeldsen-Kragh J, Haugen M, Borchgrevink CF, et al. Controlled trial of fasting and one year vegetarian diet in rheumatoid arthritis. Lancet. 12 Oct 1991;338(8772):899–902.
